Abstract Multiscale simulations using the quasicontinuum (QC) method with the embedded-atom method (EAM) potential are performed to examine the mechanical response of Cu–Ag bilayer film during nanoindentation tests. An attempt is made, from the viewpoint of collective interaction among misfit dislocations on the interface, to account for the strengthening and weakening mechanisms of interface on Cu–Ag bilayer film. The details of misfit dislocation nucleation, motion and collective interaction on Cu/Ag and Ag/Cu interfaces are discussed systematically, respectively. The investigation shows that the property and performance of Cu–Ag bilayer film mainly depend on the mechanical property of upper film. Both the strengthening and weakening effects are closely related to the collective interaction among misfit dislocations on the interface. Due to the pinning effect of interface on misfit dislocation, both the local interface migration and the voids can be observed at the core region of misfit dislocations. For nanoindentation on Cu/Ag bilayer film, the plastic deformation is localized chiefly in the lower Ag substrate and the void will disappear with the redistribution of misfit dislocations, which indicate that there are distinct protective and strengthening effects of the upper Cu film on the lower Ag substrate. While, for nanoindentation on Ag/Cu bilayer film, both the upper Ag film and the lower Cu substrate experience plastic deformation and the voids will not disappear, which imply that there are an obvious weakening effect of the upper Ag film on the lower Cu substrate. In addition, the multiscale simulation results are consistent with the experimental results.